Jalloul Wael, Ghizdovat Vlad, Saviuc Alexandra, Jalloul Despina, Grierosu Irena Cristina, Stefanescu Cipriana
Department of Biophysics and Medical Physics-Nuclear Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iasi, Romania.
North East Regional Innovative Cluster for Structural and Molecular Imaging (Imago-Mol), 700115 Iasi, Romania.
Pharmaceuticals (Basel). 2025 Aug 18;18(8):1215. doi: 10.3390/ph18081215.
Targeted alpha therapy (TAT) has recently emerged as a highly promising approach for the management of metastatic castration-resistant prostate cancer (mCRPC), especially in patients with disease progression despite standard treatments. Among alpha-emitter radiopharmaceuticals, actinium-225-labelled prostate-specific membrane antigen ([225Ac]Ac-PSMA) has shown remarkable potential due to its high linear energy transfer (LET), short path length, and ability to induce potent, localised cytotoxic effects. This review summarises current clinical evidence regarding [225Ac]Ac-PSMA radioligand therapy (RLT), emphasising its efficacy, safety profile, and position relative to beta-emitter therapy with lutetium-177 ([177Lu]Lu-PSMA). Data from compassionate-use programs and small clinical trials demonstrate that [225Ac]Ac-PSMA produces significant biochemical and imaging responses, including > 50% declines in prostate-specific antigen (PSA) and lesion regression on [68Ga]Ga-PSMA PET/CT, even in heavily pre-treated mCRPC cohorts. Xerostomia, renal toxicity, and haematological adverse effects remain the main safety challenges, necessitating optimisation of patient selection, dosing strategies, and salivary gland protection protocols. Compared with [177Lu]Lu-PSMA, [225Ac]Ac-PSMA appears effective even in cases of beta-refractory disease, highlighting its complementary role rather than a competitive alternative. However, limited availability, high production costs, and the lack of large-scale, randomised trials hinder widespread clinical adoption. Future directions include combination protocols, improved radiopharmaceutical design, and trials evaluating its use in earlier disease stages. This review provides a comprehensive overview of the clinical aspects of [225Ac]Ac-PSMA RLT and its evolving role in advanced prostate cancer management.
靶向α治疗（TAT）最近已成为治疗转移性去势抵抗性前列腺癌（mCRPC）的一种极具前景的方法，尤其是对于那些尽管接受了标准治疗但疾病仍进展的患者。在α发射体放射性药物中，225锕标记的前列腺特异性膜抗原（[225Ac]Ac-PSMA）因其高线性能量传递（LET）、短路径长度以及诱导强效局部细胞毒性作用的能力而显示出显著潜力。本综述总结了关于[225Ac]Ac-PSMA放射性配体疗法（RLT）的当前临床证据，重点强调了其疗效、安全性概况以及相对于177镥（[177Lu]Lu-PSMA）β发射体疗法的地位。来自同情用药项目和小型临床试验的数据表明，即使在经过大量预处理的mCRPC队列中，[225Ac]Ac-PSMA也能产生显著的生化和影像学反应，包括前列腺特异性抗原（PSA）下降超过50%以及[68Ga]Ga-PSMA PET/CT上的病灶消退。口干、肾毒性和血液学不良反应仍然是主要的安全挑战，需要优化患者选择、给药策略和唾液腺保护方案。与[177Lu]Lu-PSMA相比，[225Ac]Ac-PSMA即使在β难治性疾病的情况下似乎也有效，突出了其互补作用而非竞争性替代作用。然而，可用性有限、生产成本高以及缺乏大规模随机试验阻碍了其在临床上的广泛应用。未来的方向包括联合方案、改进放射性药物设计以及评估其在疾病早期阶段使用的试验。本综述全面概述了[225Ac]Ac-PSMA RLT的临床方面及其在晚期前列腺癌管理中不断演变的作用。
